U.S. patent number 4,666,885 [Application Number 06/699,702] was granted by the patent office on 1987-05-19 for combination therapy for treatment of female breast cancer.
Invention is credited to Fernand Labrie.
United States Patent |
4,666,885 |
Labrie |
May 19, 1987 |
Combination therapy for treatment of female breast cancer
Abstract
A method of treatment of breast cancer in susceptible animals
whose ovarian hormonal secretions are blocked by surgical or
chemical means, e.g., by use of an LH-RH agonist, e.g.,
[D-Trp.sup.6, des-Gly-NH.sub.2.sup.10 ]LH-RH ethylamide with a
therapy comprising administering an antiandrogen, e.g., flutamide
and an optionally, an inhibitor of adrenal sex steroid biosynthesis
e.g., aminoglutethimide, pharmaceutical compositions useful for
such treatment and two, four and five component pharmaceutical kits
containing such compositions are disclosed.
Inventors: |
Labrie; Fernand (St-Foy,
Quebec, G1W 1Z9, CA) |
Family
ID: |
24810514 |
Appl.
No.: |
06/699,702 |
Filed: |
February 8, 1985 |
Current U.S.
Class: |
514/10.3;
930/130; 930/20; 930/21 |
Current CPC
Class: |
A61K
31/445 (20130101); A61K 31/495 (20130101); A61K
38/04 (20130101); A61K 31/445 (20130101); A61K
31/495 (20130101); A61K 38/04 (20130101); Y10S
514/80 (20130101); Y10S 930/13 (20130101); A61K
2300/00 (20130101); A61K 2300/00 (20130101); A61K
2300/00 (20130101) |
Current International
Class: |
A61K
38/04 (20060101); A61K 31/445 (20060101); A61K
31/495 (20060101); A61K 037/24 () |
Field of
Search: |
;260/112.5R ;514/15 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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637389 |
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Mar 1964 |
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BE |
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58481 |
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Aug 1982 |
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EP |
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78158 |
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May 1983 |
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EP |
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Other References
Cancer Research 42, 4788-4791 (1982). .
J. Steroid Biochem., vol. 19, No. 1, pp. 999-1007 (1983). .
J. of Steroid Biochem., vol. 14, pp. 819-822 (1981). .
Nature, vol. 313 (1985), pp. 231-233. .
Cancer Treatment Reports, vol. 68 (No. 1), pp. 281-289 (1984), A.
V. Schally et al. .
Proc. Natl. Acad. Sci. USA, vol. 80, pp. 1459-1462 (1983), T. W.
Redding and A. V. Schally. .
"LH-RH Analogs in the Treatment of Human Breast Cancer", H. A.
Harvey et al., in LHRH and Its Analogs-A New Class of Contraceptive
and Therapewtic Agents, pp. 329-335, (B. H. Vickery et al. etc.)
MTP Press Lancaster VIC/1192. .
Doll, R., et al., Cancer Incidence in Five Continents, II
Springer-Verlag, (UICC Publications, New York) 1970. .
Wang, D. Y. et al., Europ. J. Cancer (1976) vol. 12, pp. 951-958.
.
Adams, J. B., Cancer (1977), vol. 40, pp. 325-333. .
Wong, D. Y., et al., Europ. J. Cancer (1975), vol. 11, pp. 873-879.
.
Secreto, G., et al., Europ. J. Cancer. Clin. Oncol. (1983), vol.
19, pp. 5-10. .
F. Labrie et al., "Inhibition of Testicular and Ovarian Functions
by LHRH Agonists," In: Bioregulators of Reproduction, (1982)
Academic Press, pp. 305-341. .
Meldrum, D. R., et al., J. Clin. Endocrinol. Metab., (1982), vol.
54, pp. 1081-1083. .
Nicholson, R. I., et al. Reviews in Endocrine-Related Cancer
(1984), Nicholson, R. I. and Griffins, K., eds). .
Klijn, J. G. and De Jong, F. H., The Lancet (1982), pp. 1213-1216.
.
J. Steroid Biochem., vol. 20 (No. 6B) 1381 (1984), J. G. M. Klijn
et al. .
J. Med. Chem., vol. 21 1018-1024 (1978), A. S. Dutta et al. .
Biochem. Biophy. Res. Commun., vol. 100, pp. 915-920 (1981) J.
Erchegg, et al. .
Endrocrinology, vol. 110, pp. 1445-1447 (1982); D. H. Coy et al.
.
J. Steroid. Biochem., vol. 20 (No. 6B), 1366 (1984); J. J. Nestor
et al. .
J. Steroid Biochem., vol. 20, (No. 6B) 1365 (1984); J. Rivier et
al. .
J. Steroid Biochem., vol. 20 (No. 6B) p. 1369 (1984); A. Corbin et
al. .
LH-RH and Its Analogs (B. H. Vickery et al. Editors), pp. 3-10, J.
J. Nestor. .
LH-RH and Its Analogs (B. H. Vickery et al. Editors), pp. 11-22, J.
Rivier et al. .
LH-RH and Its Analogs (B. H. Vickery et al. Editors) pp. 23-33, J.
J. Nestor et al. .
"Solid Phase Peptide Synthesis", Stewart et al. Freman and Co., San
Francisco, CA. (1969), pp. 1-26. .
J. Med. Chem., vol. 19, pp. 423-425 (1976) D. H. Coy et al. .
Trams, G. and Maass, S. H., Cancer Res. (1977), vol. 37, pp.
258-261. .
Flax, H. et al., The Lancet (1973) pp. 1204-1207. .
Wagner, R. K. and Jungblut, P. W., Acta Endocrinologica (1976),
vol. 82, pp. 105-120. .
Matsumoto, K. et al. Hormonal Regulators of Mammary Tumors (1984),
B. S. Leung ed.; Eden Press, Inc. (1984), pp. 216-244. .
Lancet, 1, 1213-1216 (1982), J. G. M. Klijn et al., (The Lancet,
May 29, 1982). .
Cancer, vol. 50, 1708-1712 (1982), A. V. Buzdar et al. .
Lancet, 1204-1207 (1973), H. Flax et al. (The Lancet; Jun. 2,
1973). .
The Prostate, vol. 4, 579-594 (1983), F. Labrie et al. .
Cancer Treatment Review, vol. 5, 131-141 (1978), H. Movridsen et
al. .
J. L. Hayward et al., Cancer (Mar. 1977), vol. 39, pp. 1289-1294.
.
C. Huggins et al., Ann. Surg. (1945), vol. 122, pp. 1031-1041.
.
C. Huggins et al., JAMA (1951), vol. 147, pp. 101-1-6. .
A. A. Fracchia et al., Surg. Gynecol. Obstet (1967), vol. 125, pp.
747-756. .
H. S. Harris et al., Cancer (1969), vol. 24, pp. 145-151. .
Brown, P. W., et al., Arch. Surg. (1975), vol. 110, pp. 77-81.
.
Silverstein, M. J. et al., Surgery, (1975), vol. 77, pp. 825-832.
.
Smith, I. E., et al., Brit. Med. J. (1981), vol. 283, pp.
1432-1434. .
Buzdar, A. V. et al., Cancer (1982), vol. 50, pp. 1708-1712. .
Santen, R. J., et al., New. Engl. J. Med., (1981), vol. 305, pp.
545-551. .
Seymour-Munn, K. and Adams, J., Endocrinology (1983), vol. 112, pp.
486-491. .
Reed, M. J. et al., Cancer Research (1983), vol. 43, pp. 3940-3943.
.
Labrie, F. et al., Raven Press, (in press), J. G. M. Kijn, ed.
.
Seqi, M., et al. Sendai, Tokoku University School of Medicine
(1969)..
|
Primary Examiner: Phillips; Delbert R.
Attorney, Agent or Firm: Hoffman; Thomas D. Rosen; Gerald
S.
Claims
What is claimed:
1. A method of treating breast cancer in a warm-blooded female
animal in need of such treatment which comprises blocking the
ovarian hormonal secretions of said animal by surgical or chemical
means and in association therewith administering to said animal a
therapeutically effective amount of an antiandrogen or
pharmaceutical compositions thereof.
2. The method of claim 1 wherein the ovaries are surgically
removed.
3. The method of claim 1 wherein the ovarian hormonal secretions
are blocked by administering an amount of a LH--RH agonist or a
LH--RH antagonist or a pharmaceutical composition thereof effective
to block said hormonal secretions.
4. The method according to claim 1 wherein the LH--RH agonist is
administered parenterally together with a pharmaceutically
acceptable parenteral carrier.
5. The method of claim 1 wherein the antiandrogen is administered
orally, together with a pharmaceutically acceptable oral
carrier.
6. The method of claim 1 wherein the LH--RH agonist is a
nonapeptide or a decapeptide represented by the formula:
L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-p
rolyl-Z, wherein X is D-tryptophyl, D-leucyl, D-alanyl,
iminobenzyl-D-histyl, 3-(2-naphthyl)-D-alanyl,
O-tert-butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or
N-methyl-D-alanyl and wherein Y is L-leucyl, D-leucyl,
N.sup..alpha. -methyl-D-leucyl, N.sup..alpha. -methyl-L-leucyl or
D-alanyl and wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein
R.sub.1 is H, lower alkyl or haloloweralkyl.
7. The method of claim 1 wherein the LH--RH agonist or LH--RH
antagonist is administered as a subcutaneous depot injection.
8. The method of claim 1 wherein the antiandrogen is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
9. The method of claim 1 wherein the antiandrogen is
4'-nitro-3'-trifluoromethylisobutyranilide.
10. A method of treating breast cancer in a castrated warm-blooded
female animal having breast cancer which comprises administering to
said animal a therapeutically effective amount of an association of
an antiandrogen and at least one inhibitor of sex steroid
biosynthesis or pharmaceutical compositions thereof.
11. The method of claim 10 wherein the ovaries have been surgically
removed.
12. The method of claim 10 wherein the ovarian hormonal secretions
are blocked by administering an amount of a LH--RH agonist or a
LH--RH antagonist or a pharmaceutical composition thereof effective
to block said hormonal secretions.
13. The method of claim 10 which further comprises administering
hydrocortisone or pharmaceutical compositions thereof.
14. The method of claim 10 wherein the antiandrogen and at least
one inhibitor of sex steroid biosynthesis are each administered
orally, together with a pharmaceutically acceptable oral
carrier.
15. The method of claim 10 wherein the inhibitor of sex steroid
biosynthesis is aminoglutethimide or a pharmaceutical composition
thereof.
16. The method of claim 10 wherein the inhibitor of sex steroid
biosynthesis is ketoconazole or a pharmaceutical composition
thereof.
17. The method of claim 10 wherein the antiandrogen is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
18. The method of claim 10 wherein the antiandrogen is
4'-nitro-3'-trifluoromethylisobutyranilide.
19. A method of treating breast cancer in a warm-blooded female
animal having breast cancer which comprises administering to said
animal a therapeutically effective amount of an association of a
LH--RH agonist or a LH--RH antagonist, an antiandrogen and at least
one inhibitor of sex steroid biosynthesis or pharmaceutical
compositions thereof.
20. The method of claim 19 wherein the LH--RH agonist is
administered parenterally together with a pharmaceutically
acceptable parenteral carrier.
21. The method of claim 19 wherein the inhibitor(s) of sex steroid
biosynthesis and the antiandrogen are each administered orally,
together with pharmaceutically acceptable oral carrier.
22. The method of claim 19 wherein the LH--RH agonist is
administered at a daily parenteral dose of between about 250 and
500 .mu.g.
23. The method of claim 19 wherein the antiandrogen is administered
at a daily oral dose of between about 0.20 and 40 mg/kg and the
inhibitor of steroid formation is administered at a daily oral dose
of between about 0.20 and 40 mg/kg.
24. The method of claim 19 wherein one inhibitor of sex steroid
biosynthesis or a pharmaceutical composition thereof is
administered.
25. The method of claim 24 wherein the inhibitor of sex steroid
biosynthesis is ketoconazole or a pharmaceutical composition
thereof.
26. The method of claim 24 wherein the inhibitor of sex steroid
biosynthesis is aminoglutethimide or a pharmaceutical composition
thereof.
27. The method of claim 19 wherein two inhibitors of sex steroid
biosynthesis or pharmaceutical composition thereof are
administered.
28. The method of claim 27 wherein the two inhibitors of steorid
biosynthesis are aminoglutethimide and ketoconazole or
pharmaceutical compositions thereof.
29. The method of inhibiting the growth of breast tumors in a warm
blood female animal whose ovarian hormonal secretions have been
previously blocked by surgical or chemical means which comprises
administering to the warm-blooded animal having such tumors a
therapeutically effective amount of an association of an
antiandrogen, hydrocortisone and an inhibitor of adrenal sex
steroid biosynthesis, or pharmaceutical compositions thereof.
30. The method of claim 29 wherein the ovaries have been surgically
removed.
31. The method of claim 29 wherein the ovarian hormonal secretions
are blocked by administering an amount of a LH--RH agonist or a
LH--RH antagonist or a pharmaceutical composition there of
effective to block said hormonal secretions.
32. The method of claim 31 wherein the antiandrogen and an
inhibitor of adrenal sex steroid biosynthesis are each administered
orally together with a pharmaceutically acceptable oral
carrier.
33. The method of claim 29 wherein the antiandrogen is
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethylimidazoline-2,5-dione.
34. The method of claim 29 wherein the antiandrogen is
4'-nitro-3'-trifluoromethylisobutyranilide.
Description
CROSS-REFERENCE TO RELATED APPLICATION
This application is related to U.S. patent application Ser. No.
636,883, filed on August 2, 1984.
BACKGROUND OF THE INVENTION
This invention relates to a method of treatment of breast cancer in
susceptible warm-blooded female animals including humans using a
therapy comprising administering an antiandrogen to such animals
after the hormone output of their ovaries has been blocked by
surgical or chemical means. The invention also includes
pharmaceutical compositions useful for such treatment and
pharmaceutical kits containing such compositions. In its most
preferred aspect, this invention relates to treatment of breast
cancer in warm-blooded animals by parenterally administering an
LH--RH agonist or LH--RH antagonist, in association with orally
administering an antiandrogen and orally administering an
antiestrogen and orally administering an inhibitor of sex steroid
biosynthesis.
While various investigators have been studying hormone-dependent
breast and prostate cancer, none have proposed the combination
therapy of this invention.
A. V. Schally et al., Cancer Treatment Reports, 68, (No. 1) 281-289
(1984), summarize the results of animal and clinical studies on
growth inhibition of hormone-dependent mammary and prostate tumors
by use of analogues of luteinizing hormone-releasing hormones, the
so-called LH--RH agonists and suggest that LH--RH analogs and/or
antagonists may have potential for treating breast cancer.
T. W. Redding and A. V. Schally, Pro. Natl. Acad. Sci. USA, 80,
1459-1462 (1983), disclose reduction of estrogen-dependent mammary
tumors in rats and mice by use of an LH--RH agonist, [D-Trp.sup.6
]LH--RH or of two specific antagonists.
In U.S. Pat. No. 4,071,622, it is disclosed that use of certain
LH--RH agonists causes regression of DMBA-induced mammary carcinoma
in rats.
In U.S. Pat. No. 4,472,382, it is disclosed that certain LH--RH
agonists alone may be useful in the treatment of prostate
adenocarcinoma and hormone-dependent mammary tumors. While the use
of certain LH--RH agonists and an antiandrogen are disclosed for
treatment of prostate adenocarcinoma and benign prostate
hypertrophia, there is no disclosure or suggestion of the present
invention.
Some clinical improvement in premenopausal women with breast cancer
by use of the two LH--RH agonists, Buserelin and Leuprolide, is
also reported by H. A. Harvey et al. "LH--RH analogs in the
treatmemt of human breast cancer", LH--RH and Its Analogs--A New
Class of Contraceptive and Therapeutic Agents (B. H. Vickery and J.
J. Nestor, Jr., and E. S. E. Hafez, eds) Lancester, MTP Press,
(1984) and by J. G. M. Klijn et al. "Treatment with luteinizing
hormone releasing hormone analogue (Buserelin) in premenopausal
patients with metastatic breast cancer", Lancet, 1, 1213-1216
(1982).
Treatment of advanced breast cancer with aminoglutethimide after
therapy with the antiestrogen, Tamoxifen is disclosed by A. V.
Buzdar et al., Cancer, 50, 1708-1712 (1982).
H. Flax et al., Lancet, 1204-1207, (1973), suggest some women's
breast cancers are androgen-dependent.
F. Labrie et al., The Prostate, 4, 579-594 (1983), disclose that
use of a combination therapy of an LH--RH agonist (Buserelin) and
an antiandrogen (Anandron) to treat advanced prostate cancer in
previously untreated patients effects simultaneous elimination of
androgens of both testicular and adrenal origin.
F. Labrie et al., J. Steroid Biochem., 19, 99-1007 (1983), disclose
the treatment of prostate cancer by the combined administration of
an LH--RH agonist and an antiandrogen. Labrie et al. disclose
animal and clinical data in support of the proposition that the
combined LH--RH/antiandrogen treatment neutralizes the stimulatory
influence of all androgens on the development and growth of
androgen-dependent prostatic cancer.
In U.S. Pat. No. 4,094,994, it is disclosed that the use of
antiestrogens such as meso-3,4-bis(3'-hydroxyphenyl)hexane inhibits
MCF7 human breast tumor cells. In fact, the inhibitory activity of
the antiestrogen was antagonized by estradiol.
H. Mouridsen et al,. Cancer Treatment Review 5, 131-141, (1978),
disclose that Tamoxifen, an antiestrogen is effective in remission
of advanced breast cancer in about 30% of the patients treated.
J. G. M. Klijn et al., (J. Steroid Biochem, Vol. 20 (No. 6B), 1381
(1984), disclose the combined use of the antiestrogen, Tamoxifen,
and the LH--RH agonist, Buserelin, for treatment of breast cancer
is known, but objective remission of such cancers remains low
(35%).
BRIEF DESCRIPTION OF THE INVENTION
In its broadest aspect, the invention provides a method of treating
breast cancer in a warm-blooded female animal in need of such
treatment which comprises blocking the ovarian hormonal secretions
of said animal by surgical or chemical means and in association
therewith, administering to said animal a therapeutically effective
amount of an antiandrogen or a pharmaceutical composition thereof.
In one aspect, the invention provides a method of treating breast
cancer in a castrated warm-blooded female animal, i.e., such a
female animal whose ovaries were previously blocked by surgical or
chemical means from secreting estrogen, which comprises
administering to such a female in need of such treatment an
antiandrogen in association with at least one inhibitor of sex
steroid biosynthesis and, optionally, an antiestrogen, or
pharmaceutical compositions thereof, in amounts sufficient to treat
breast cancer. By completely blocking sex steroids (androgens and
estrogens) production and/or action, the present invention provides
a method of inhibiting the growth of hormone-sensitive breast
tumors in warm-blooded animals having such tumors.
In female mammals, the ovaries may be surgically removed
(oophorectomy) but preferably the secretion of estrogens from the
ovaries is blocked by chemical castration by administering an
effective amount of an LH--RH agonist or antagonist. Thus, in a
preferred aspect, the present invention provides a method of
treating breast cancer in a warm-blooded female animal, which
comprising administering to such a female in need of such treatment
an LH--RH agonist or antagonist, in association with an
antiandrogen and at least one inhibitor of sex steroid
biosynthesis, or pharmaceutical compositions thereof, in amounts
sufficient to treat breast cancer.
In its preferred aspect, the LH--RH agonist is administered
parenterally (subcutaneously or intramuscularly) and, in
association therewith, the antiandrogen and the inhibitor of sex
steroid biosynthesis are each administered orally. The invention
also provides kits or single packages combining the two, four and
five separate preferred pharmaceutical compositions; the two
component kit provides the antiandrogen oral pharmaceutical
composition and the LH--RH agonist or LH--RH antogonist parenteral
composition; the four component kit provides the LH--RH agonist or
LH--RH antagonist parenteral pharmaceutical composition, the
antiandrogen oral pharmaceutical composition and, the sex steroid
biosynthesis inhibitor oral pharmaceutical composition and the
hydrocortisone oral pharmaceutical composition and the five
component kit provides the LH--RH agonist or LH--RH antagonist
parenteral pharmaceutical composition, the antiandrogen oral
pharmaceutical composition, the antiestrogen oral pharmaceutical
composition, the sex steroid biosynthesis inhibitor oral
composition and the hydrocortisone oral pharmaceutical
composition.
Thus, this invention provides a novel method for effective
treatment of breast cancer, in the absence of an antiestrogen. In
addition, the amounts of antiestrogen required when administered in
association with this combined therapy are lower than normally used
in prior art methods, e.g., J. G. M. Klijn et al., J. Steroid
Biochem. 20 (No. 6B) 1381 (1984), to treat breast cancer, and thus,
the harmful effects of relatively large doses of antiestrogen are
minimized.
DETAILED DESCRIPTION OF THE INVENTION
In one preferred aspect, the present invention provides an
effective method of treating breast cancer in warm-blooded female
animals in need of such treatment by administering an LH--RH
agonist or antagonist, in association with an antiandrogen and an
inhibitor of sex steroid biosynthesis or pharmaceutical
compositions thereof in amounts sufficient to inhibit breast tumor
growth. These active compounds can be administered together or in
any order as discussed hereinafter. To assist in determining the
effect of the treatment, blood plasma concentrations of the sex
steroids of adrenal origin, i.e., adrenal androgens and estrogens,
and tumor size are measured. Lowered concentrations of sex steroids
and reduction in tumor size are indicative of successful treatment,
e.g. inhibition of tumor growth using active compounds described
herein in accordance with the present invention. The concentrations
of adrenal androgens and estrogens such as dehydroepiandrosterone
(DHEA), DHEA-sulfate (DHEAS), androst-5-ene-3.beta., 17.beta.-diol
(.DELTA..sup.5 -diol) and, the ovarian estrogen, 17.beta.-estradiol
(E.sub.2) are measured by standard methods well known to those
skilled in the art, see for example F. Labrie et al., The Prostate,
4, 579-594 (1983).
The change in tumor size is measured by standard physical methods
well known to those skilled in the art, e.g., bone scan, chest
X-ray, skeletal survey, ultrasonography of the liver and liver scan
(if needed), CAT-scan and physical examination.
While a LH--RH agonist or a LH--RH antagonist may be used in one
preferred aspect of the present invention, the use of a LH--RH
agonist is more preferred.
By the term "LH--RH agonist" is meant synthetic analogues of the
natural luteinizing hormone-releasing hormone (LH--RH), a
decapeptide of the structure:
L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-glycyl-L-leucyl-L-
arginyl-L-prolylglycyl-NH.sub.2
Typical suitable LH--RH agonists include nonapeptides and
decapeptides represented by the formula:
L-pyroglutamyl-L-histidyl-L-tryptophyl-L-seryl-L-tyrosyl-X-Y-L-arginyl-L-pr
olyl-Z
wherein X is D-tryptophyl, D-leucyl, D-alanyl,
iminobenzyl-D-histidyl, 3-(2-naphthyl)-D-alanyl,
O-tert-butyl-D-seryl, D-tyrosyl, D-lysyl, D-phenylalanyl or
N-methyl-D-alanyl and Y is L-leucyl, D-leucyl, N.sup..alpha.
-methyl-D-leucyl or N.sup..alpha. -methyl-L-leucyl or D-alanyl and
wherein Z is glycyl-NHR.sub.1 or NHR.sub.1 wherein R.sub.1 is H,
lower alkyl or haloloweralkyl. Lower alkyl includes straight or
branched chain alkyls having 1 to 6 carbon atoms, e.g., methyl,
ethyl, propyl, pentyl or hexyls, iso-butyl, neopentyl and the like.
Haloloweralkyl includes straight and branched chain alkyls of 1 to
6 carbon atoms having a halogen substituent, e.g.,
--CF.sub.3,--CH.sub.2 CF.sub.3,--CF.sub.2 CH.sub.3. Halogen means
F, Cl, Br, with F being preferred.
Preferred nonapeptides wherein Y is L-leucyl and X is an optically
active D-form of selected amino acids and Z is NHC.sub.2 H.sub.5
are [D-Trp.sup.6, des-gly-NH.sub.2.sup.10 ]-LH--RH ethylamide
(X=D-Trp.sup.6); [D-Ser-(t-BuO).sup.6, des-gly-NH.sub.2.sup.10
]-LH--RH ethylamide [X=D-Ser(t-BuO.sup.6)]; [D-Leu.sup.6,
des-gly-NH.sub.2.sup.10 ]-LH--RH ethylamide (X=D-Leu.sup.6);
[D-His(Bzl).sup.6, des-gly-NH.sub.2.sup.10 ]-LH--RH ethylamide
(X=iminobenzyl-D-His.sup.6) and [D-Ala.sup.6,
des-gly-NH.sub.2.sup.10 ]-LH--RH ethylamide (X=D-Ala.sup.6).
Preferred decapeptides include [D-Trp.sup.6 ]-LH--RH wherein
X=D-Trp, Y=L-leucyl, Z=glycyl-NH.sub.2, [D-Phe.sup.6 ]-LH--RH
wherein X=D-phenylalanyl, Y=L-leucyl and Z=glycyl-HN.sub.2) or
[D-Nal(2).sup.6 ]-LH--RH which is [(3-(2-naphthyl)-D-Ala.sup.6
]-LH--RH wherein X=3-(2-naphthyl)-D-alanyl, Y=L-leucyl and
Z=glycyl-NH.sub.2.
Other LH--RH agonists useful within the scope of this invention are
the .alpha.-aza analogues of the natural LH--RH, especially,
[D-Phe.sup.6, Azgly.sup.10 ]-LH--RH, [D-Tyr(Me).sup.6, Azgly.sup.10
]-LH--RH, and [D-Ser-(t-BuO).sup.6, Azgly.sup.10 ]-LH--RH disclosed
by A. S. Dutta et al. in J. Med. Chem., 21, 1018 (1978) and U.S.
Pat. No. 4,100,274 as well as those disclosed in U.S. Pat. Nos.
4,024,248 and 4,118,483.
Typical suitable LH--RH antagonists include
[N-Ac-D-p-Cl-Phe.sup.1,2, D-Phe.sup.3, D-Arg.sup.6, D-Ala.sup.10
]-LH--RH disclosed by J. Ercheggi et al., Biochem. Biophys. Res.
Commun. 100, 915-920, (1981); [N-Ac-D-p-Cl-Phe.sup.1,2,
D-Trp.sup.3, D-Arg.sup.6, D-Ala.sup.10 ]LH--RH disclosed by D. H.
Coy et al., Endocrinology, 110: 1445-1447, (1982);
[N-Ac-D-(3-(2-naphthyl)-Ala).sup.1, D-p-Cl-Phe.sup.2, D-Trp.sup.3,
D-hArg(Et.sub.2).sup.6, D-Ala.sup.10 ]-LH--RH and [N-Ac-Pro.sup.1,
D-p-F-Phe.sup.2, D-(3-(2-naphthyl)Ala.sup.3,6 ]-LH--RH disclosed by
J. J. Nestor et al. J. Steroid Biochem., 20 (No. 6B), 1366 (1984);
the nona- and decapeptide LH--RH analogs useful as LH--RH
antagonists disclosed in U.S. Pat. No. 4,481,190 (J. J. Nestor et
al.); analogs of the highly constrained cyclic antagonist, cycle
[.DELTA..sup.3 Pro.sup.1, D-p-Cl-Phe.sup.2, D-Trp.sup.3,6,
N-Me-Leu.sup.7,.beta.-Ala.sup.10 ]-LH--RH disclosed by J. Rivier,
J. Steroid Biochem., 20, (No. 6B), 1365 (1984), and
[N-Ac-D-(3-(2-naphthyl)-Ala.sup.1, D-p-F-Phe.sup.2, D-Trp.sup.3,
D-Arg.sup.6 ]-LH--RH disclosed by A. Corbin et al., J. Steroid
Biochem. 20 (No. 6B) 1369 (1984).
Other LH--RH agonist and antagonist analogs are disclosed in LH--RH
and Its Analogs (B. H. Vickery et al.) at pages 3-10 (J. J. Nestor)
and pages 11-22 (J. Rivier et al.) and pages 23-33 (J. J. Nestor et
al.).
The LH--RH agonists and antagonists useful in this invention may
conveniently be prepared by the method described by Stewart et al.
in "Solid Phase Peptide Synthesis" (published in 1969 by Freeman
& Co., San Francisco, page 1) but solution phase synthesis may
also be used.
The nona- and decapeptides used in this invention are conveniently
assembled on a solid resin support, such as 1% cross-linked
Pro-Merrifield resin by use of an automatic peptide synthesizer.
Typically, side-chain protecting groups, well known to those in the
peptide arts, are used during the dicyclohexylcarbodiimidecataylzed
coupling of a tert-butyloxycarbonylamino acid to the growing
peptide attached to a benzhydrylamine resin. The
tert-butyloxycarbonyl protecting groups are removed at each stage
with trifluoroacetic acid. The nona- or decapeptide is cleaved from
the resin and deprotected by use of HF. The crude peptide is
purified by the usual techniques, e.g., gel filtration and
partition chromatography and optionally lyophilization. See also D.
H. Coy et al., J. Med. Chem. 19, pages 423-425, (1976).
Typical suitable antiandrogens include non-steroidal antiandrogens
such as the imidazolidines, especially
1-(3'-trifluoromethyl-4'-nitrophenyl)-4,4-dimethyl-imidazoline-2,5-dione
(also called Anandron) described in U.S. Pat. No. 4,097,578, or
4'-nitro-3'-trifluoromethylisobutyranilide (also called flutamide)
described in U.S. Pat. No. 4,329,364 as well as the
N-(phenylalkanoyl)aniline derivatives disclosed in U.S. Pat. No.
4,386,080 and the 3,4- disubstituted - branched - chain
acylanilides disclosed in U.S. Pat. No. 4,239,776 (A. T. Glen et
al.). Flutamide is the preferred antiandrogen.
Typical suitable steroidal antiandrogens include
6-chloro-1,2-dihydro-17-(acetyloxy)-3'H-cyclopropa[1,2]pregna-1,4,6-triene
-3,20-dione, available under the tradename of Androcur from
Schering A.G., W. Berlin,
17-(acetyloxy)-6-methyl-pregna-4,6-diene-3,20-diene, also called
megestrol acetate and available from Mead Johnson & Co.,
Evansille, Ind. under the tradename of Megace.
Typical suitable antiestrogens include those steroidal and
non-steroidal antiestrogens such as
(1RS,2RS)-4,4'-diacetoxy-5,5'-difluoro-(1-ethyl-2-methylene)di-m-phenylene
diacetate, which is available from Biorex under the tradename of
Acefluranol, 6.alpha.-chloro-16.alpha.-methylpregn-4-ene-3,20-dione
which is available from Eli Lilly & Co., Indianapolis, Ind.
under the tradename of Clometherone,
6-chloro-17-hydroxypregna-1,4,6-triene-3,20-dione which is
available as the acetate salt from Syntex Labs, Palo Alto, Cal. as
Delmadione Acetate,
17-hydroxy-6-methyl-19-norpregna-4,6-diene-3,20-dione which is
available from Theramex under the name of Lutenyl,
1-[2-[4-[1-(4-methoxyphenyl)-2-nitro-2-phenylethenyl]phenoxy]ethyl]-pyrrol
idine which is available as the citrate salt from Parke-Davis Div.
of Warner-Lambert Co., Morris Plains, N.J. under the name of
Nitromifene Citrate, substituted aminoalkoxyphenylalkenes such as
(Z)-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine
which is available as the citrate salt from Stuart Pharmaceuticals,
Wilmington, Del. as Tamoxifen Citrate (see also Belgian Pat. No.
637,389, Mar. 1964), 3,4-dihydro-2-(p-methoxyphenyl)- 1-naphthyl
p-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone which is available as the
methane sulfonate salt from Eli Lilly & Co. under the tradename
of Trioxifene Mesylate,
1-[4'-(2-dimethylaminoethoxy)-phenyl)-1-(3'-hydroxyphenyl)-2-phenyl-but-1-
ene, which is available from Klinge Pharma,
6-hydroxy-2-(p-hydroxyphenyl)-benzo(b)thien-3-yl[2-(1-pyrrolidinyl)-ethoxy
phenyl]ketone which is available from Eli Lilly & Co.
(LY-117018),
[6-hydroxy-2-(4-hydroxyphenyl)benzo(b)thien-3-yl]-[4-(2-(1-piperdinyl)-eth
oxy)phenyl]methanone, which is available from Eli Lilly & Co.
as the hydrogen chloride salt (LY-156758) and
meso-3,4-bis(3'-hydroxyphenyl)hexane as well as the dimethyl,
dipropyl and 3'-acetoxyphenyl analogues which are described in U.S.
Pat. No. 4,094,994 and a series of 1-phenyl-alkane and -alkenes,
e.g. (E)-3-cyclopentyl-1-(4-hydroxyphenyl)-1-phenyl-1-butene and
2-cyclopentyl-1-[4-hydroxy- or
methoxyphenyl]-3-phenyl-2-propen-1-ol and FC-1157 which is
available as the citrate salt from Farmos Group, Ltd., Turku,
Finland (see also Eur. Pat. Appln. No. EP 78,158). FC-1157,
LY-117018, LY-156578 and Tamoxifen are the preferred antiestrogens.
A pure antiestrogen is more preferred.
The inhibitors of sex steroid biosynthesis found useful in the
present invention include those compounds which inhibit
biosynthesis of sex steroids and precursor sex steroids of adrenal
origin, preferably of ovarian and adrenal origin.
Thus, in another preferred aspect of the present invention, an
inhibitor of sex steroid biosynthesis such as
3-(4-aminophenyl)-3-ethyl-2,6-piperidinedione which is commonly
called aminoglutethimide, which is an inhibitor of sex steroid
biosynthesis of adrenal but also ovarian origin and which is
available from Ciba Pharmaceutical Co., Summit N.J. under tradename
Cytadren, or ketoconazole which is available from Janssen
Pharmaceutica, Piscataway, N.J. under the tradename Nizoral is
administered in combination with the LH--RH agonist or antagonist,
the antiandrogen and optionally the antiestrogen for treatment of
breast cancer.
When an inhibitor of adrenal sex steroid biosynthesis, e.g.,
aminoglutethimide is administered, cortisol biosynthesis is
blocked. Accordingly, hydrocortisone is administered in
physiological amounts sufficient to maintain normal glucocorticoid
levels.
In this invention, the association of the LH--RH agonist or
antagonist, antiandrogen and the inhibitor of steroid biosynthesis
and hydrocortisone and optionally antiestrogen are administered as
pharmaceutical compositions via topical, parenteral or oral means.
The LH--RH agonist or antagonist is administered parenterally,
i.e., intramuscularly, subcutaneously or intravenously by injection
or infusion by nasal drops or intra-vaginally by suppository. The
LH--RH agonist or antagonist also may be microencapsulated in or
attached to a biocompatable, biodegradable polymer, e.g.,
poly(d,l-lactide-coglycolide) and subcutaneously or intramuscularly
injected by a technique called subcutaneous or intramuscular depot
to provide continuous, slow release of the LH--RH agonist or
antagonist over a period of 30 days or longer. The most preferred
route of administration of the LH--RH agonist or antagonist is
subcutaneous depot injection. Preferably the antiandrogen and
antiestrogen (when used) will each be administered orally.
Preferably the inhibitor of sex steroid biosynthesis, e.g.
aminoglutethimide and/or ketoconazole are administered orally.
The amount of each component administered is determined by the
attending clinicians taking into consideration the etiology and
severity of the disease, the patient's condition and age, the
potency of each component and other factors.
The LH--RH agonist or antagonist is generally administered at from
about 10 to 5000 .mu.g per day, with contemplated dosage ranges of
about 10 to 1500 .mu.g per day and about 200 to 500.mu. per day for
the LH--RH agonist, and about 50-5000 .mu.g per day for the LH--RH
antagonist being preferred.
In the most preferred embodiment of this invention, the LH--RH
agonist or antagonist is administered subcutaneously in a daily
dose of about 500 .mu.g for the first 30 days and thereafter
subcutaneously in a daily dose of about 250 .mu.g regardless of the
patients' body weight. When the LH--RH agonist or antagonist is
administered, once every 30-day period or even longer, by
intramuscular or subcutaneous depot injection, a dose from about
300 to 150000 .mu.g per 30-day period is used, with a dose of about
750 to 15000 .mu.g per 30-day period being preferred.
The antiandrogen compositions are generally administered in a
dosage range of about 0.20 to 40 mg/kg (body weight) per day with
750 mg per day in three equally divided doses being preferred.
The antiestrogen compositions (when used) are administered in a
dosage range of about 0.1 to 10 mg/kg body weight per day, with 10
mg in two equally divided doses being preferred.
The aminoglutethimide compositions when used are administered
initially in a dosage of about 250 mg given at 8-hour intervals and
the dosage may be increased in increments of about 250 mg daily up
to a total daily dose of about 2 grams.
The hydrocortisone compositions are administered orally in a dosage
range of about 0.1 to 20 mg/kg body weight per day. Preferably, the
hydrocortisone is administered orally at the dose of about 10 mg in
the morning and about 5 mg doses in the afternoon and in the
evening.
The ketoconazole compositions when used are administered orally in
a dose of about 250 mg given at 8-hour intervals and may be
increased to about 2 grams per day.
The LH--RH agonist or antagonist and antiandrogen and and inhibitor
of sex steroid bisoynthesis and antiestrogen (when used) each may
be administered separately or when the modes of administration are
the same, all or two of them may be administered in the same
composition, but in any case the preferred ratio of LH--RH agonist
to antiandrogen to antiestrogen to inhibitor of sex steroid
biosynthesis administered daily will be about 250 .mu.g of LH--RH
agonist to about 750 mg of antiandrogen to about 15 mg of
antiestrogen to about 750 mg of sex steroid biosynthesis
inhibitor.
In the most preferred aspect of this invention, the LH--RH agonist
is [D-Trp.sup.6,des-Gly NH.sub.2.sup.10 ]LH--RH ethylamide which is
administered subcutaneously in single daily dose of about 500 .mu.g
for the first thirty (30) days of treatment and thereafter in a
single daily dose of about 250 .mu.g; the antiandrogen is
4'-nitro-3'-trifluoromethyl-isobutyranilide, i.e., flutamide, which
is administered orally in three equally divided daily doses of
about 250 mg; the inhibitor of sex steroid biosynthesis is
ketoconazole or aminoglutethimide which is administered orally in
three equally divided daily doses of about 250 mg; the
hydrocortisone is administered orally at a dose of about 10 mg in
the morning and two equally divided doses of about 5 mg, 8 and 16
hours thereafter. The antiestrogen, when used, is
(Z)-2-[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethyl ethylamine
(Tamoxifen) which is administered orally in three equally divided
doses of about 10 mg every 12 hours.
The inhibitor of steroid biosynthesis and antiandrogen are
preferably administered to a female in need of the breast cancer
treatment of this invention one or two days before the LH--RH
agonist or antagonist is administered, but the attending clinician
may elect to start administration of the LH--RH agonist or
antagonist, the antiandrogen and the inhibitor of sex steroid
biosynthesis on the first day of the treatment.
When patients whose ovaries have already been removed are treated
according to this invention, the antiandrogen and the inhibitor(s)
of steriod biosynthesis such as aminoglutethimide and or
ketoconazole administration and dosage are the same as indicated
when the antiandrogen or the association of the antiandrogen and
inhibitor(s) of sex steroid biosynthesis are used in combination
with the LH--RH agonist or antagonist as well as the optional
ingredient, the antiestrogen.
The LH--RH agonists or antagonists useful in the present invention
are typically amorphous solids which are freely soluble in water or
dilute acids, e.g., HCl, H.sub.2 SO.sub.4, citric, acetic, mandelic
or fumaric. The LH--RH agonist or antagonist for subcutaneous
injection is supplied in vials containing 6 mL of sterile solution
with the LH--RH agonist or antagonist at a concentration of about
1.0 mg/mL.
A typical pharmaceutical composition of the LH--RH agonist or
antagonist include the LH--RH agonist or antagonist or a
pharmaceutically acceptable acid salt thereof, benzyl alcohol, a
phosphate buffer (pH=6.9-7.2) and sterile water.
The LH--RH agonist or antagonist for intramuscular or subcutaneous
depot injection may be microencapsulated in a biocompatible,
biodegradable polymer, e.g., poly (d,l-lactide-co-glycolide) by a
phase separation process or formed into a pellet. The microspheres
may then be suspended in a carrier to provide an injectable
preparation or the depot may be injected in the form of a pellet.
See also European Patent Application EPA No. 58,481 published Aug.
25, 1982 for solid compositions for subdermal injection or
implantation or liquid formulations for intramuscular or
subcutaneous injections; containing biocompatible, biodegradeable
polymers such as lactide-glycolide copolymer and an LH--RH agonist,
e.g., D-Ser-t-BuO.sup.6, Azgly.sup.10 -LH--RH.
The aminoglutethimide and ketoconazole and hydrocortisone are
typically compounded in customary ways for oral administration,
e.g., in tablets, capsules and the like.
The antiandrogens useful in the present invention are typically
formulated with conventional pharmaceutical excipients, e.g., spray
dried lactose and magnesium stearate into tablets or capsules for
oral administration. The antiestrogens, when used with the
invention, are typically compounded in customary ways for oral
administration, e.g., in capsules, tablets, as dragees or even in
liquid form, e.g., suspensions or syrups. One or more of the active
substances, with or without additional types of active agents, can
be worked into tablets or dragee cores by being mixed with solid,
pulverulent carrier substances, such as sodium citrate, calcium
carbonate or dicalcium phosphate, and binders such as polyvinyl
pyrrolidone, gelatin or cellulose derivatives, possibly by adding
also lubricants such as magnesium stearate, sodium lauryl sulfate,
"Carbowax" or polyethylene glycols. Of course, taste-improving
substances can be added in the case of oral-administration
forms.
The therapeutically active antiestrogen compound should be present
in a concentration of about 0.5-90% by weight of the total mixture,
i.e., in amounts that are sufficient for maintaining the
above-mentioned dosage range.
As further forms of administration, one can use plug capsules,
e.g., of hard gelatin, as well as closed soft-gelatin capsules
comprising a softener or plasticizer, e.g., glycerine. The plug
capsules contain the active substance preferably in the form of a
granulate, e.g., in mixture with fillers, such as lactose,
saccharose, mannitol, starches, such as potato starch or
amylopectin, cellulose derivatives or highly-dispersed silicic
acids. In soft-gelatin capsules, the active substance is preferably
dissolved or suspended in suitable liquids, such as vegetable oils
or liquid polyethylene glycols.
In place of oral administration, all the active compounds may be
administered parenterally. In such case, one can use a solution of
the active substance, e.g., in sesame oil or olive oil.
Following the above treatment using the described regimen, breast
tumor growth is inhibited and in some instances complete remission
occurs.
* * * * *